Tshooj 1: Kev Tiv Thaiv Lub Raum Nrog SGLT2 Inhibitors: Cov Teeb Meem Hauv Cov Kab Mob Raum Mob thiab Mob Raum

Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com

Abstract

Lub hom phiaj ntawm Kev Tshawb Fawb: Qhov kev tshuaj xyuas no muab cov lus piav qhia tseem ceeb ntawm cov pov thawj tshwm sim uas sodium-glucose co-trans-porter-2(SGLT2) inhibitors exert nephroprotective teebmeem rau cov neeg mob ntshav qab zib hom 2.

Cov kev tshawb pom tsis ntev los no Lub SGLT2 inhibitor chav kawm ntawm cov neeg ua haujlwm txo qis cov piam thaj tsis ntev los no tau pom tias muaj txiaj ntsig zoo los txo qhov pib thiab kev loj hlob ntawm lub raum teeb meem hauv cov neeg muaj thiab tsis muaj ntshav qab zib. Randomized soj ntsuam kev sim thiab 'lub ntiaj teb tiag' kev soj ntsuam kev tshawb fawb, feem ntau cuam tshuam nrog cov neeg mob ntshav qab zib hom 2, tau sau tseg tias kev siv SGLT2 inhibitor tuaj yeem ua rau txo qis hauv glomerular filtration rate (GFR), txo qhov pib ntawm microalbuminuria, thiab qeeb lossis thim rov qab. kev loj hlob ntawm proteinuria.

Cov ntsiab lus: Cov teebmeem nephroprotective ntawm SGLT2 inhibitors yog cov teebmeem hauv chav kawm pom nrog txhua tus neeg ua haujlwm pom zoo hauv cov neeg uas muaj GFR ib txwm muaj lossis tsis zoo. Cov kev cuam tshuam no kuj tau pom nyob rau hauv cov neeg uas tsis muaj ntshav qab zib, lean, thiab cov neeg tsis muaj zog uas qhia tias cov txheej txheem txuas ntxiv dhau ntawm cov piam thaj txo qis, txo qhov hnyav, thiab txo cov ntshav siab uas nrog lawv cov txiaj ntsig glucosuric hauv cov neeg mob ntshav qab zib. Ib lub tswv yim tseem ceeb yog cov lus tawm tswv yim tubuloglomerular uas SGLT2 inhibitors ua rau muaj sodium ntau dhau los ntawm nephron: cov sodium tau hnov ​​​​los ntawm macula hlwb uas ua los ntawm adenosine kom txwv tsis pub muaj glomerular arterioles, yog li tiv thaiv glomeruli los ntawm kev txo qis intraglomerular siab. Lwm cov teebmeem ntawm SGLT2 inhibitors txhim kho tubular oxygenation thiab metabolism thiab txoraum mobthiab fibrosis. SGLT2 inhibitors tsis tau nce qhov kev pheej hmoo ntawm cov kab mob urinary los yog kev pheej hmoo ntawmmob raum raug mob. Txawm li cas los xij, kev qhia txog SGLT2 inhibitor hauv cov neeg mob uas muaj GFR qis heev tsis tau txhawb nqa vim yog qhov pib poob hauv GFR, thiab nws yog qhov yuav tsum tau txiav txim siab kho yog tias muaj mob raum mob, hypovolemia, lossis hypotension.

Ntsiab lus: Sodium-glucose co-transporter-2(SGLT2)inhibitors.Diabetic raum kab mob.Chronic raum kab mob. Albuminuria. Mob raum mob

Nyem qhov no kom paub seb cistanche siv rau dab tsi

Taw qhia

Sodium-glucose co-transporter-2(SGLT2)inhibitors yog cov tshuaj txo cov piam thaj uas tshem tawm cov piam thaj ntau dhau los ntawm cov nyhuv glucosuric los ntawm kev txo cov piam thaj reabsorption ntawm lub raum filtrate[1,2e]. Txij li thaum cov thawj SGLT2 inhibitor nyob rau hauv 2012, cov chav kawm tau loj hlob mus rau xws li canagliflozin, dapagliflozin, empagliflozin, thiab ertugliflozin nyob rau hauv cov teb chaws Europe thiab Americas, nrog rau ntxiv cov tswv cuab ntawm cov chav kawm tau tsim nyob rau hauv lwm lub cheeb tsam (Table 1). Txawm hais tias tsim los txo qis hyperglycemia thiab pab tswj lub cev hnyav hauv hom 2 mob ntshav qab zib, tam sim no cov kev kho mob ntxiv tau lees paub rau SGLT2 inhibitors los daws cov teeb meem ntawm lub raum thiab cov kab mob ntawm cov ntshav qab zib hom 2.

Thawj qhov kev txhawj xeeb txog SGLT2 inhibitors tsom mus rau qhov muaj feem cuam tshuam rau lub raum, tshwj xeeb tshaj yog muaj kab mob genito-urinary, cuam tshuam rau lub zais zis, thiab ua rau mob raum mob hnyav [3]. Nws kuj tau sau tseg nrog kev txaus siab tias kev tswj hwm ntawm SGLT2 inhibitor ua rau poob qis ib ntus hauv glomerular pom tus nqi thiab ua rau tsis tu ncua ntawm cov ntshav ntim thiab ntshav siab. Txawm li cas los xij, kev soj ntsuam thaum lub sijhawmmob plawvCov txiaj ntsig kev sim siab thiab kev tshawb fawb hauv ntiaj teb tiag tiag tau txheeb xyuas qhov muaj txiaj ntsig zoo ntawm SGLT2 inhibitors kom txo tau qhov kev pheej hmoo ntawm kev pib thiab kev loj hlob ntawm ntau yam mob plawv thiab khaws cia.lub raum ua haujlwm.

Cov lus piav qhia no, uas yog ua raws li kev tshuaj xyuas cov ntaub ntawv dav dav (Box 1), muaj kev ntsuam xyuas tseem ceeb ntawm cov pov thawj tshwm sim rau nephroprotective zog ntawm SGLT2 inhibitors. Kauj Ruam 1 Kev Tshawb Fawb Kev Tshawb Fawb thiab cov txheej txheem xaiv. MEDLINE, PubMed, thiab Google Scholar tau tshawb nrhiav cov ntawv luam tawm thaum Lub Ib Hlis 2010 thiab Lub Peb Hlis 2021 siv cov ntsiab lus 'sodium-glucose transporter inhibitor, 'SGLT2 inhibitor thiab cov npe dav dav ntawm tus neeg SGLT2 inhibitors ua ke nrog lub sijhawm ' kab mob raum', ' mob raum mob, 'mob raum mob', 'lub raum ua haujlwm', 'mob ntshav qab zib thiab' hom 2 mob ntshav qab zib. Cov kev tshawb fawb tau raug xaiv yog tias lawv tau ua nyob rau hauv tib neeg cov pej xeem thiab / lossis piav qhia txog cov txheej txheem kho mob, luam tawm ua lus Askiv, thiab muab cov ntaub ntawv cog lus. Cov ntaub ntawv xov xwm, cov ntawv kho, cov lus qhia, thiab cov kev tshawb fawb hauv tsev kho mob tau suav nrog thaum lawv muab cov ntaub ntawv lossis kev txhais lus tsis muaj nyob hauv lwm qhov chaw.

SGLT2 Inhibition

Txoj kev loj hlob ntawm SGLT2 inhibitors tuaj yeem taug qab los ntawm lub xyoo pua puas xyoo kev soj ntsuam uas cov glucoside phlorizin ua rau glucosuria [4]. Cov kev tshawb fawb ua ntej xyoo 1980 tau pom tias kev kho phlorizin tuaj yeem tswj hwm hyperglycemia nyob rau hauv ib feem ntawm cov nas pancreatectomised, tab sis daim ntawv thov kev kho mob tos cov tshuaj analogs uas evaded plab hnyuv glucosidase degradation thiab muab kev txhim kho potency thiab xaiv los inhibit SGLT2 es tsis yog SGLT1 [5,6]

SGLT2 pom yuav luag tsuas yog nyob rau hauv lub luminal daim nyias nyias ntawm epithelial hlwb nyob rau hauv lub thib ib thiab thib ob ntu ntawm lub proximal tubules, qhov uas nws mediates lub reabsorption ntawm feem ntau (feem ntau ntau tshaj los yog sib npaug rau 90 feem pua) ntawm lim piam thaj (Fig.1).SGLT1 nyob rau hauv lub luminal daim nyias nyias ntawm cov hlwb nyob rau hauv lub thib peb (ncaj) ntu ​​ntawm lub proximal tubules mediates reabsorption ntawm tsawg concentrations ntawm qabzib nyob rau hauv lub tubule. SGLT1 muaj ntau tshaj plaws nyob rau hauv lub apical daim nyias nyias ntawm enterocytes qhov twg nws mediates qabzib uptake los ntawm txoj hnyuv lumen. Txhawm rau kom tsis txhob cuam tshuam nrog txoj hnyuv nqus ntawm cov piam thaj, kev xaiv siab rau inhibition ntawm SGLT2 feem ntau tau nyiam (Table 1). Txawm li cas los xij, canagliflozin siv qee qhov kev txwv ntawm SGLT1, thiab sotagliflozin yog SGLT1/2 inhibitor: ob qho tib si ntawm cov neeg ua haujlwm no tuaj yeem ncua lub plab zom mov ntawm cov piam thaj ua ntej absorbed los yog degraded, uas pab prandial glycemic tswj. Tus nqi ntawm cov tshuaj no uas tau nqus thiab raug rau lub raum, thaum inhibiting SGLT2, tsis txaus kom muaj qhov cuam tshuam loj heev ntawm SGLT1 hauv cov tubules ze.

Fig.1 Cov chaw tseem ceeb ntawm kev ua ntawm sodium-glucose co-transporter (SGLT) inhibitors. SGLT2 (encoded los ntawm cov khoom siv tshuaj lom neeg cov noob slcSa2) tau nthuav tawm yuav luag tag nrho hauv luminal membrane ntawm epithelial hlwb hauv ob sab ntawm thawj thiab thib ob ntawm cov tubules ze. Nws yog lub peev xwm loj thauj mus los ua ke nrog sodium-glucose stoichiometry ntawm 1: 1 los kho cov reabsorption ntawm feem ntau ntawm cov piam thaj hauv lim. SGLT1 (encoded los ntawm slcSal) yog qhia nyob rau hauv lub luminal membrane ntawm hlwb nyob rau hauv lub thib peb (ncaj) ntu ​​ntawm lub proximal tubules. Nws ua nrog sodium-glucose stoichiometry ntawm 2: 1 thiab muaj lub peev xwm qis dua tab sis muaj kev sib raug zoo dua li SGLT2 kom khaws cov piam thaj tsawg hauv cov tubule. SGLT1 tau nthuav tawm dav thiab tshwm sim feem ntau nyob rau hauv cov apical daim nyias nyias ntawm enterocytes hauv cov hnyuv me uas nws kho cov piam thaj los ntawm txoj hnyuv lumen. Ob qho tib si thauj khoom yog cov active symporters uas nyob ntawm seb cov sodium gradient tsim los ntawm Na plus -K十-ATPase twj tso kua mis nyob rau hauv lub basolateral daim nyias nyias uas txo cov intracellular sodium concentration. Glucose uas tau coj los ntawm sodium-glucose co-transporters mus rau hauv cov tubules ze ze thiab cov enterocytes raug tshem tawm thoob plaws lub basolateral daim nyias nyias thiab mus rau hauv lub interstitium los ntawm kev yooj yim glucose transporters (xws li GLUT1 thiab GLUT2)

Lub hyperglycemia ntawm ntshav qab zib txhais tau hais tias ntau dua li cov piam thaj ib txwm raug lim los ntawm glomeruli mus rau hauv cov tubules ze ze, thiab cov nyiaj ntau ntxiv tau rov ua dua, cuam tshuam nrog kev them nyiaj rov qab ntawm SGLT2 thiab SGLT1 qhia [9]. Txawm li cas los xij, lub raum pib rau cov piam thaj feem ntau ua txhaum cai, thiab cov glucosuria tau txhim kho los ntawm SGLT2 inhibitors uas ua los ntawm kev sib tw thim rov qab yam tsis tau thauj lawv tus kheej [2e]. Lawv khi rau cov co-transporters ntawm lub luminal nto nrog affinity ntau dua li qabzib thiab nrog lub sij hawm nyob ntawm ob peb feeb. Yog li, qhov tsis tseem ceeb (kho kho) cov ntsiab lus ntawm SGLT inhibitor hauv cov lim dej tuaj yeem tiv thaiv kom tsis txhob rov nqus ntawm qhov loj (txog li 100 g / hnub) ntawm cov kua nplaum lim. Txawm hais tias SGLT2 inhibitors txo qis lub raum pib rau cov piam thaj, lawv cov txiaj ntsig glucosuric yog qhov txwv tus kheej, uas lawv tsis ua rau muaj kev pheej hmoo ntawm kev kho mob hypoglycemia. Qhov no yog vim hais tias, raws li tus inhibitor nce glucosuria, qhov no txo ​​cov ntshav qabzib kom qis dua cov piam thaj, thiab cov neeg ua haujlwm txaus (tsis muaj tshuaj tiv thaiv) tuaj yeem rov qab nqus (yuav luag tag nrho cov piam thaj tsawg dua, uas tiv thaiv cov ntshav qabzib los ntawm kev poob qis hauv qab euglycemia.

Glucose Lowering thiab Weight Lowering Cov kev ua ntawm SGLT2 inhibitors yog ywj siab ntawm insulin raws li txoj cai, piv txwv li tsis txo qis los ntawm insulin tsis kam lossis tsis muaj insulin kiag li, ua kom cov piam thaj txo qis hauv hom 2 thiab ntshav qab zib hom 1. Kev vam khom ntawm hyperglycemia txhais tau hais tias kev txo qis cov piam thaj ntau dua rau cov tib neeg uas muaj ntshav qabzib ntau dua thiab tshwj xeeb tshaj yog muaj txiaj ntsig zoo hauv kev txo qis cov piam thaj mus ncig. Meta-analyses ntawm qhov txo qis hauv HbAlc nrog SGLT2 inhibitors hauv hom 2 mob ntshav qab zib mellitus tau sau tseg tsis tu ncua ntawm kev txo qis ntawm 0.5 mus rau 1 feem pua ​​(6-11 mmol/mol) los ntawm qhov pib ntawm ib ncig ntawm 8 feem pua ​​(64 mmol/ mol)[10-12]. Vim tias SGLT2 inhibitors muaj qhov sib txawv ntawm kev ua haujlwm dua li lwm cov tshuaj txo cov piam thaj, lawv tuaj yeem siv nrog lwm cov tshuaj xws li insulin, thiab feem ntau tuaj yeem txo cov tshuaj insulin uas xav tau hauv hom 2 thiab hom 1 ntshav qab zib [13,14]. Txawm li cas los xij, SGLT2 inhibitors tsis tuaj yeem hloov qhov kev xav tau ntawm cov tshuaj insulin txaus los txhawb nqa cov kev xav tau ntawm metabolic. Kev txo qis ntawm (lossis qeeb hauv kev pib) insulin feem ntau yog vim li cas rau atypical (euglycaemic) ntshav qab zib ketoacidosis (DKA) uas DKA tshwm sim tsis muaj hyperglycemia thiab qee zaum qhia tias kev kuaj mob ntshav qab zib hom 2 yog hom 1 [15].

In clinical trials with type 2 diabetes patients, the weight-reducing effect of SGLT2 inhibitors has typically been around 3 kg, leveling out by 6-12 months, although 'real-world observational studies have often noted reduc-tions>6 kg uas txuas ntxiv dhau ib xyoos. Kev poob phaus feem ntau yog vim muaj calorie poob los ntawm glucosuria Table 2 Loj randomized tswj cov hlab plawv cov txiaj ntsig kev sim (CVOTs) uas lub raum cov xwm txheej tau ntsuas thaum kho cov neeg mob ntshav qab zib hom 2 nrog SGLT2 inhibitor.BMI lub cev qhov ntsuas qhov ntsuas, CVD kab mob plawv, eGFR kwv yees. glomerular filtration rate, GLD glucose-lowering drug, MACE qhov teeb meem loj ntawm cov hlab plawv (mob plawv tuag, tsis tuag myocardial infarction lossis stroke), MI myocardial infarction, UACR zis albumin-creatinine piv. Cov txiaj ntsig rau MACE, CV tuag, MI, mob stroke, plawv tsis ua haujlwm, tag nrho cov neeg tuag, thiab lub raum sib xyaw yog qhov phom sij nrog 95 feem pua ​​​​ntawm kev ntseeg siab.* Lub raum sib txawv ntawm qhov kev sim: EMPA-REG txo cov adipose loj, txawm tias txo cov ntshav plasma kuj tuaj yeem pab txhawb. [16, 17] ib.

Table2 Large randomized controlled cardiovascular outcome trials(CVOTs)in which renal events were measured during treatment of type 2 diabetes patients with an SGLT2 inhibitor.BM7 body mass index, CVD cardiovascular disease,eGFR estimated glomerular filtration rate, GLD glucose-lowering drug, MACE major adverse cardiovascular event(cardiovascular death, non-fatal myocardial infarction or stroke), MI/ myocardial infarction, UACR urine albumin-creatinine ratio. Values for MACE, CV death, MI, stroke, heart failure, all deaths, and renal composite are hazard ratios with 95% confidence intervals.*Renal composites varied between trials: EMPA-REG OUTCOMES.doubling of serum creatinine,eGFR≤45 ml/min/1.73 m², start renal replacement, renal death; CANVAS PROGRAM,>40% decrease in eGFR, start renal replacement, renal death: DECLARE,>40% decrease in eGFR,end-stage kidney disease, renal or CV death; VERTIS, doubling of serum creatinine, start renal replacement, renal death; CREDENCE, double serum creatinine,end-stage kidney disease, renal death or CV death: SCORED, sustained (>30 days)decrease of≥50%in eGFR, dialysis, and renal transplantation or sustained (>30 hnub) eGFR ntawm<15 ml/min/1.73="" m².**decline="" in="" the="" long-term="" rate="" of="">

Cov teebmeem plawv

Beyond glucose-lowering and weight lowering, SGLT2 inhibitors have consistently reduced blood pressure (systolic by 3-5 mmHg and diastolic by 2-3 mmHg)during clinical trials without causing hypotension [18]. SGLT2 inhibitors have also OUTCOMES, doubling of serum creatinine, eGFR≤45 ml/min/1.73 m², start renal replacement, renal death; CANVAS PROGRAM,>40% decrease in eGFR, start renal replacement, renal death: DECLARE,>40% decrease in eGFR, end-stage kidney disease, renal or CV death; VERTIS, doubling of serum creatinine, start renal replacement, renal death; CREDENCE, double serum creatinine,end-stage kidney disease, renal death or CV death; SCORED, sustained(>30 days)decrease of≥50% in eGFR, dialysis, and renal transplantation or sustained(>30 hnub) eGFR ntawm<15 ml/min/1.73="" m².**declinein="" long-term="" rate="" of="" egfr="" consistently="" reduced="" the="" risk="" of="" new="" heart="" failure="" and="" worsening="" of="" existing="" heart="" failure="" during="" clinical="" trials="" (table2).="" the="" benefit="" is="" evident="" within="" a="" few="" weeks="" of="" starting="" an="" sglt2="" inhibitor,="" occurs="" in="" people="" with="" and="" without="" diabetes,="" and="" is="" independent="" of="" the="" extent="" of="" effects="" on="" glucose,="" weight,="" or="" blood="" pressure[19-21].="" the="" improved="" prognosis="" for="" heart="" failure="" is="" also="" independent="" of="" age="" and="" is="" not="" significantly="" affected="" by="" the="" presence="" of="" ckd,="" albuminuria,="" or="" concomitant="" use="" of="" antihypertensive="" therapies.="" studies="" in="" which="" ejection="" fraction="" was="" quantified="" have="" mostly="" involved="" patients="" with="" reduced="" ejection="" fraction(hfref),="" but="" there="" is="" emerging="" evidence="" that="" sglt2="" inhibitors="" can="" also="" benefit="" those="" with="" preserved="" and="" mid-range="" ejection="" fraction.[22-25].measures="" of="" atherosclerotic="" cardiovascular="" disease(cardiovascular="" deaths,="" non-fatal="" myocardial="" infarction,="" and="" stroke)="" have="" also="" been="" reduced="" in="" some="" studies="" with="" sglt2="" inhibitors:="" these="" are="" reviewed="" in="" detail="" elsewhere="" in="" the="" context="" of="" the="" reciprocating="" interrelationships="" of="" heart="" and="" kidney="">

Mob ntshav qab zib raum

Txhua hom ntshav qab zib muaj feem cuam tshuam nrog kev pheej hmoo siab ntawm lub raum tsis ua haujlwm (xws li mob ntshav qab zib nephropathy lossis mob ntshav qab zib raum (DKD)). Qhov no feem ntau lees paub los ntawm kev mob raum tsis yooj yim (CKD) nrog qhov kwv yees glomerular filtration rate (eGFR)<60 ml/min/1.73m²that="" can="" be="" attributed="" to="" diabetes="" [28].="" the="" condition="" may="" be="" accompanied="" by="" micro-(uacr="" 30-300="" mg/g)or="" macro-(="">300 mg/g) albuminuria, often with an underlying glomerulopathy of thickened capillary basement membranes, diffuse mesangial sclerosis, and nodular sclerosis. The normal age-related rate of decline in eGFR（~1 ml/min/l.73m²per year wheneGFR>60 ml / min / 1.73m²) feem ntau yog muab ob npaug rau hauv hom 2 mob ntshav qab zib mellitus nrog CKD thiab tuaj yeem tshaj 3 ml / min / 1.73m² ib xyoos rau cov neeg uas muaj macroalbuminuria [29]. Cov kev tshawb fawb soj ntsuam qhia tias 20-40 feem pua ​​​​ntawm cov neeg mob ntshav qab zib hom 2 ua rau muaj eGFR<60 ml/min/1.73m²,="" mostly="" amongst="" older="" patients="" and="" those="" with="" poor="" glycaemic="" control.="" type="" 2="" diabetes="" is="" also="" a="" major="" cause="" of="" end-stage="" kidney="" disease(eskd)="" requiring="" renal="" replacement="" therapy="">

Cov kev kho mob ib txwm muaj (feem ntau nruj tswj ntshav siab nrog ACE inhibitors lossis ARBs thiab tswj cov ntshav qabzib hnyav) txo qhov kev loj hlob ntawm DKD, tab sis lawv tsis tuaj yeem tiv thaiv kev kis kab mob. Cov pov thawj muaj txiaj ntsig tam sim no qhia tau hais tias SGLT2 inhibitors tuaj yeem tiv thaiv qhov pib ntawm DKD thiab kev ua haujlwm qeeb qeeb ntawm nws tus kheej thiab ntxiv rau kev thaiv ntawm renin-angiotensin-aldosterone system (RAAS).

Kab mob raum thiab siv SGLT2 Inhibitors

Vim tias qhov txo qis hauv GFR txo cov piam thaj xa mus rau hauv cov tubules ze, qhov ua tau zoo ntawm cov piam thaj (thiab yog li kev ua haujlwm ntawm cov tshuaj tiv thaiv hyperglycemic) ntawm SGLT2 inhibitors poob kwv yees li ntawm txoj kab nrog kev poob qis hauv GFR.Vim li ntawd, cov ntawv sau rau SGLT2 inhibitors txhais GFR tus nqi. hauv qab no uas nws tau pom zoo kom tsis txhob pib lossis kho ntxiv [35-38]. Nrog rau kev txaus siab ntxiv tias SGLT2 inhibitors tsis cuam tshuam rau lub raum kev nyab xeeb thiab muab cov txiaj ntsig cardio-lub raum, cov lus qhia thiab kev tso cai eGFR ntau yam tau nthuav dav (Table 3) thiab sib txawv ntawm lub tebchaws.

Lub raum Endpoints

Kev lees paub tias SGLT2 inhibitors tuaj yeem hloov kho cov kab mob ntshav qab zib hauv lub raum tau pib clouded los ntawm kev soj ntsuam luv luv tsom rau qhov pib poob hauv eGFR. Qhov kev poob no feem ntau yog kwv yees li 5ml / min / 1.73m², ncav cuag nadir li ntawm 1-2 lub lis piam thiab maj mam rov qab los ntawm kev kho qhov tseem ceeb nyob rau tom ntej 3-9 hli (Fig.2). Txawm li cas los xij, cov pov thawj los ntawm kev sim mus sij hawm ntev hauv hom 2 mob ntshav qab zib mellitus, tshwj xeeb tshaj yog tom qab kev ua lag luam-kev kuaj mob plawv (CVOTs) tau piav qhia hauv qab no, qhia tias eGFR tom qab poob qis dua nrog kev siv SGLT2 inhibitor dua li cov placebo-kho. cov neeg mob thiab cov albuminuria tsis tshua mob hnyav.

Prespecified Secondary endpoints hauv CVOTs soj ntsuam ntau tus neeg thiab cov kev ntsuas sib xyaw ntawm lub raum ua haujlwm uas suav nrog kev nce qib ntawm albuminuria (qhia los ntawm UACR), ob npaug ntawm cov ntshav creatinine, txo qis hauv eGFR (rau ib qho<45><60 ml/min/1.73m²）,="" end-stage="" kidney="" disease,="" kidney-related="" death="" or="" renal="" replacement="" therapy="" (dialysis="" or="" transplantation).="" because="" the="" composites="" and="" the="" patient="" populations="" differed="" between="" the="" trials,="" direct="" comparisons="" are="" necessarily="" cautious.="" however,="" each="" of="" the="" composites="" that="" included="" a="" measure="" of="" the="" rate="" of="" decline="" in="" egfr="" noted="" a="" significant="" benefit="" of="" treatment="" with="" an="" sglt2="" inhibitor:="" for="" example,="" a="" decrease="" in="" adverse="" events="" by≥30%(table="" 2).="" also,="" the="" individual="" renal="" parameters="" assessed="" in="" the="" cvots="" showed="" either="" significant="" reductions="" or="" non-significant="" numerical="" reductions="" in="" the="" occurrence="" of="" adverse="" renal="" events,="" bearing="" in="" mind="" that="" the="" studies="" were="" not="" powered="" for="" renal="">

Large Randomised Trials in Type 2 Diabetes In the EMPA-REG OUTCOME trial, the renal composite （doubling of serum creatinine,eGFR≤45 ml/min/1.73 m², initiation of renal replacement therapy or death from kidney disease) was reduced by 46% in the groups receiving empagliflozin [39,40]. After the initial dip in eGFR, there was a slight annual decline in eGFR with the use of empagliflozin （0.19±0.11 ml/min/1.73 m²/year; mean±standard error）compared with a more rapid decline in the placebo group （1.67±0.13 mL/min/1.73 m²/year）. Progression to macroalbuminuria (UACR>300 mg / g) raug txo qis hauv 38 feem pua ​​​​ntawm kev siv empagliflozin, thiab tseem muaj kev txo qis hauv cov neeg mob uas muaj cov ntshav creatinine ob npaug, poob hauv eGFR kom tsawg dua lossis sib npaug li 45 ml / min / 1.73 m², thiab pib kho lub raum hloov.

Kev sim DECLARE-TIMI 58 tau pom tias kev siv dapagliflozin tau cuam tshuam nrog 47 feem pua ​​​​txo qis hauv lub raum sib xyaw ntawm qhov txo qis ntawm eGFR los ntawm ntau dua lossis sib npaug li 40 feem pua.<60 ml/min/1.73="" m²,="" new="" eskd="" or="" death="" from="" a="" renal="" cause.="" the="" decline="" in=""><60 ml/min/1.73="" m²）="" was="" 46%="" less="" with="" dapagliflozin,="" and="" there="" were="" also="" significant="" reductions="" in="" eskd="" and="" renal="" death.="" additionally,="" dapagliflozin="" decreased="" new-onset="" albuminuria="" by="" 21%="" and="" new-onset="" macroalbuminuria="" by="">

Kev soj ntsuam ua ke ntawm CANVAS thiab CANVAS-R kev sim (CANVAS program) tau sau tseg tias kev siv cov canagliflozin txo qis los ntawm 40 feem pua ​​​​ntawm lub raum sib xyaw ntawm kev txhawb nqa (22 kev ntsuas sib law liag) txo qis (los ntawm ntau dua lossis sib npaug li 40 feem pua) hauv eGFR xav tau. Lub raum hloov kho lossis tuag los ntawm lub raum ua rau [43] Kev loj hlob ntawm albuminuria (hloov ntawm ib txwm mus rau micro- lossis micro- mus rau macro-albuminuria lossis ntau dua lossis sib npaug li 30 feem pua ​​​​nce hauv micro-albuminuria) tau txo qis nrog canagliflozin los ntawm 27 feem pua, thiab ntau tus neeg mob tau txais canagliflozin pom qhov txo qis ntawm micro-los yog macro-albuminuria.

Hauv kev sim VERTIS CV, lub raum sib xyaw, uas tsis suav nrog kev ntsuas ntawm eGFR (ob npaug ntawm cov ntshav creatinine, pib kho lub raum hloov, lossis tuag los ntawm lub raum ua rau), raug lej txo los ntawm 19 feem pua ​​(tsis suav nrog qhov tseem ceeb) los ntawm Kev siv ertugliflozin [44]. Txawm li cas los xij, kev soj ntsuam cais ntawm lub raum sib xyaw suav nrog cov sus-tained Ntau dua lossis sib npaug li 40 feem pua ​​​​txo hauv eGFR, lub raum lim ntshav / hloov pauv, lossis lub raum tuag tau sau tseg 34 feem pua ​​​​txo nrog ertugliflozin, thiab los ntawm 5 xyoos, qhov poob ntawm eGFR tsawg dua (los ntawm 2.6 ml / min / 1.73 m²) dua li cov placebo. Tsis tas li ntawd, los ntawm 5 xyoos, ertugliflozin txo qhov kev loj hlob ntawm ib txwm-rau microalbuminuria los ntawm 21 feem pua ​​thiab nce regression los ntawm macro- mus rau micro- thiab los ntawm macro-los yog micro-rau normoalbuminuria los ntawm 23 feem pua.

Ntau qhov kev ntsuam xyuas ntawm lub raum cov ntaub ntawv los ntawm CVOTs saum toj no thiab lwm yam kev tshawb fawb tau lees paub tias SGLT2 inhibitors txo cov kev sib xyaw ua rau eGFR, ESKD, lossis lub raum tuag txog li 33 feem pua ​​[46-48].

Kev sim rau cov neeg uas muaj lub raum tsis zoo nyob thoob plaws plaub CVOTs tau piav qhia saum toj no, cov txiaj ntsig zoo ntawm SGLT2 inhibitor ntawm ntau lub raum tsis ua haujlwm tau tshwm sim (rau qhov ntau dua lossis tsawg dua) tsis hais poj niam txiv neej, haiv neeg, hnub nyoog, qhov hnyav, ntev, lossis qhov hnyav ntawm ntshav qab zib; muaj los yog tsis muaj kab mob plawv; thiab lub hauv paus ntawm eGFR los yog lub hauv paus albuminuria. Txawm li cas los xij, hauv cov kev tshawb fawb no, ob peb tus neeg mob tau nce CKD (egeGFR<45 ml/min/1.73="" m²）or="" advanced="" macroalbuminuria.="" this="" was="" addressed="" in="" the="" credence="" study="" in="" which="" type="" 2="" diabetes="" patients="" were="" recruited="" with="" an="" egfr="" range="" of="" 30-90="" ml/min/1.73="" m²,="" macroalbuminuria（uacr="">300 rau<5,000 mg/g),="" and="" raas="" blockade="">

Hauv CREDENCE, 60 feem pua ​​​​ntawm cov neeg mob muaj eGFR ntawm<60 ml/min/1.73="" m²,and="" 30%="" had="" anegfr=""><45ml in/1.73="" m²（mean="" baseline="" egfr="" of="" 56="" ml/min/1.73="" m2）,while="" 88%="" had="" a="" uacr="">{{0}} mg/g(median UACR 927 mg/g).Lub raum puas (ob npaug ntawm cov ntshav creatinine, ESKD, lub raum tuag, lossis CV tuag) yog 30 feem pua ​​qis dua nrog rau kev siv cov canagliflozin, thiab muaj qhov txo qis ntawm qhov txo qis hauv eGFR rau cov neeg tau txais canagliflozin piv rau cov placebo (-1.85±0.13 piv rau -4.59±0.14 ml/min/1.73 m². Yog tias qhov sib txawv ntawm kev poob qis hauv eGFR tau txuas ntxiv rau cov pej xeem zoo li no (hnub nyoog 63, eGFR 56 ml / min / 1.73 m²), nws raug suav tias yuav siv sijhawm ntev dua 10 xyoo rau cov neeg mob canagliflozin nce mus rau ESKD. [49]. Tseeb tiag, hauv CREDENCE muaj 32 feem pua ​​tsawg dua ntawm ESKD(eGFR ntawm<15 ml/min/1.73="" and/or="" renal="" replacement）="" and="" 34%="" fewer="" renal="" deaths="" with="" the="" use="" of="" canagliflozin.="" also,="" canagliflozin="" lowered="" uacr="" by="" 31%="" at="" 6="" months="" and="" increased="" by="" 30%="" the="" number="" of="" patients="" with="" a="" reduction="" in="" uacr[50].="" of="" particular="" note,="" the="" effectiveness="" of="" the="" sglt2="" inhibitor="" to="" slow="" the="" decline="" in="" egfr="" and="" reduce="" the="" progression="" of="" albuminuria="" was="" similar="" for="" patients="" with="" a="" baseline="" egfr="">los yog<45 ml/min/1.73="" m²and="" a="" uacr="">los yog<1,000 mg/g,="" and="" the="" sglt2="" inhibitor="" also="" slowed="" the="" decline="" in="" egfr="" for="" patients="" with="" a="" baseline=""><30 ml/min/1.73m².="" the="" effectiveness="" of="" the="" sglt2="" inhibitor="" on="" these="" parameters="" was="" independent="" of="" glycaemic="" status,="" type="" of="" raas="" blockade,="" and="" atherosclerotic="" cardiovascular="" disease,="" suggesting="" that="" the="" benefits="" of="" sglt2="" inhibitors="" on="" renal="" function="" can="" be="" gained="" irrespective="" of="" cardio-renal="" or="" metabolic="" status="" in="" type="" 2="">

Similar findings emerged from the SCORED trial in type 2 diabetes patients with CKD (eGFR 25-60 ml/min/1.73 m²）. Treatment with the SGLT1/2 inhibitor sotagliflozin was associated with a 29% reduction in the renal composite of sustained (>30 days) decrease of≥50% in eGFR,dial-ysis, renal transplantation or sustained(>30 hnub) eGFR ntawm<15 ml/min/1.73="">

Because the CVOTs and similar studies in type 2 diabetes indicated that the cardio-renal benefits of SGLT2 inhibitors were not contingent on their glucose-lowering efficacy, studies were undertaken in populations that included people without diabetes(Table 4).The DAPA-CKD trial examined the effect of dapagliflozin in people with(67%)and with-out(33%)type 2 diabetes who had renal impairment (eGFR 25-75ml/min/1.73 m²,mean 43.1 ml/min/1.73 m²; and UACR 200-5000 mg/g,median~950 mg/g with 48.3% of patients having a UACR>1000 mg/g)[51].Standard care for all patients included RAAS blockade. Similar reductions in the renal composite endpoint(decline in eGFR>50%, ESKD, renal death, or CV death) were observed with the use of dapagliflozin in those with (by 36%)and without(by 50%)diabetes. Dapagliflozin also reduced each of the component measures of the composite, and the findings were generally consistent for patients with an eGFR>los yog<45 ml/min/1.73="" m²or="" uacr="">los yog<1,000 mg/g.="" the="" average="" annual="" decline="" in="" egfr="" was="" also="" slower="" with="" dapagliflozin="" than="" with="" placebo="" （-1.67="" versus-3.59="" ml/min/1.73="">